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This study will evaluate the effect of treatment with multiple doses of MK-8457 on systolic blood pressure in participants with mild to moderate hypertension in addition to safety and tolerability. The study hypothesis is that MK-8457 does not increase systolic blood pressure to a clinically significant extent, as measured by 24-hour mean ambulatory systolic blood pressure change from baseline after 10 days of dosing.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| MK-8457-Placebo Sequence | Experimental | Participants received MK-8457 100 mg twice daily (BID) for 10 days followed by Placebo for 10 days. Each treatment was separated by a 10-day washout. |
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| Placebo-MK-8457 Sequence | Experimental | Participants received Placebo for 10 days followed by MK-8457 100 mg BID for 10 days. Each treatment was separated by a 10-day washout. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MK-8457 | Drug | 10 x 10-mg capsule BID for 10 days |
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| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline to Day 10 in 24-hour Mean Ambulatory Systolic Blood Pressure (SBP) | SBP was measured using ambulatory blood pressure monitoring (ABPM) on Day -1 and Day 10 of each treatment period. The 24-hour least squares (LS) mean ambulatory SBP change from baseline was then determined for Day 10, the last day of multiple dose treatment. Baseline is defined as the average 24-hour SBP for each participant on Day -1. Increased values represent an increase in hypertensive severity. | Baseline and Day 10 |
| Number of Participants Who Experienced at Least One Adverse Event (AE) | An AE is defined as any unfavorable and unintended medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. | Up to 70 days |
| Number of Participants Who Discontinued the Study Medication Due to an AE | An AE is defined as any unfavorable and unintended medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. | Up to 70 days |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline to Day 10 in 24-hour Mean Ambulatory Diastolic Blood Pressure (DBP) | DBP was measured using ambulatory blood pressure monitoring (ABPM) on Day -1 and Day 10 of each treatment period. The 24-hour LS mean ambulatory DBP change from baseline was then determined for Day 10, the last day of multiple dose treatment. Baseline is defined as the average 24-hour DBP for each participant on Day -1. Increased values represent an increase in hypertensive severity. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Director | Merck Sharp & Dohme LLC | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Call for Information | Miramar | Florida | United States | |||
| Call for Information |
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| ID | Title | Description |
|---|---|---|
| FG000 | MK-8457-Placebo Sequence | Participants received MK-8457 100 mg twice daily (BID) for 10 days followed by Placebo for 10 days. Each treatment was separated by a 10-day washout. |
| FG001 | Placebo-MK-8457 Sequence | Participants received Placebo for 10 days followed by MK-8457 100 mg BID for 10 days. Each treatment was separated by a 10-day washout. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 |
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| Period 2 |
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All participants that received treatment with either MK-8457 or Placebo in the study.
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| ID | Title | Description |
|---|---|---|
| BG000 | All Participants |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline to Day 10 in 24-hour Mean Ambulatory Systolic Blood Pressure (SBP) | SBP was measured using ambulatory blood pressure monitoring (ABPM) on Day -1 and Day 10 of each treatment period. The 24-hour least squares (LS) mean ambulatory SBP change from baseline was then determined for Day 10, the last day of multiple dose treatment. Baseline is defined as the average 24-hour SBP for each participant on Day -1. Increased values represent an increase in hypertensive severity. | The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (change in 24-hour mean ambulatory SBP). | Posted | Least Squares Mean | 95% Confidence Interval | mmHg | Baseline and Day 10 |
|
Up to 70 days
The safety population consisted of all participants who received at least one dose of the investigational drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | MK-8457 100 mg BID | Participants received MK-8457 100 mg BID for 10 days |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lymphadenopathy | Blood and lymphatic system disorders | MedDRA v 15.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Vice President, Global Clinical Development | Merck Sharp & Dohme Corp. | 1-800-672-6372 | ClinicalTrialsDisclosure@merck.com |
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| ID | Term |
|---|---|
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| Placebo for MK-8457 | Drug | 10 x 10-mg capsule BID for 10 days |
|
| Baseline and Day 10 |
| Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours | The effect of drug on resting blood pressure was estimated using maxMAΔ. The maxMAΔ in blood pressure was calculated as the maximum moving average change from baseline to Day 10 of 3 consecutive 15-minute blood pressure measurements across the first 4 hours after the morning (AM) and evening (PM) doses. In this method, the LS means of three consecutive time points over the 4 hour period were determined and the maximum LS mean was used for the endpoint. Blood pressure was determined using continuous monitoring at rest. Increased values represent an increase in hypertensive severity. | Up to 4 hours postdose on Days 1 and 10 |
| Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours (AUC0-12hr) of MK-8457 | AUC0-12hr is an estimate of total plasma exposure to study drug over the dosing interval (12hr). Plasma concentrations of MK-8457 were determined on Day 1 (after initial dosing) and Day 10 (after multiple dosing). The placebo group is not included; this endpoint evaluated only the MK-8457 group. | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10 |
| Maximum Concentration (Cmax) of MK-8457 | Maximum plasma concentrations of MK-8521 were determined for the AM dose on Day 1 and Day 10. The placebo group was not included; this endpoint evaluated only the MK-8457 group. | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; 24 hrs post-AM dose on Day 10 |
| Time to Maximum Concentration (Tmax) of MK-8457 | Tmax was determined for the AM dose on Day 1 and Day 10. The placebo group was not included; this endpoint evaluated only the MK-8457 group. | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; 24 hrs post-AM dose on Day 10 |
| Trough Plasma Concentration (Ctrough) of MK-8457 | The lowest plasma concentration reached by the drug prior to the next administration was determined for Day 1 (after initial dosing) and Day 10 (after multiple dosing). The placebo group was not included; this endpoint evaluated only the MK-8457 group. | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; pre-AM dose on Day 5 or 6 |
| Tacoma |
| Washington |
| United States |
| NOT COMPLETED |
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| Years |
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| Age, Customized | Number | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| OG001 | Placebo | Participants received Placebo for 10 days followed by MK-8457 100 mg BID for 10 days. Each treatment was separated by a 10-day washout. |
|
|
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| Secondary | Change From Baseline to Day 10 in 24-hour Mean Ambulatory Diastolic Blood Pressure (DBP) | DBP was measured using ambulatory blood pressure monitoring (ABPM) on Day -1 and Day 10 of each treatment period. The 24-hour LS mean ambulatory DBP change from baseline was then determined for Day 10, the last day of multiple dose treatment. Baseline is defined as the average 24-hour DBP for each participant on Day -1. Increased values represent an increase in hypertensive severity. | The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (change in 24-hour mean ambulatory DBP). | Posted | Least Squares Mean | 95% Confidence Interval | mmHg | Baseline and Day 10 |
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| Secondary | Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours | The effect of drug on resting blood pressure was estimated using maxMAΔ. The maxMAΔ in blood pressure was calculated as the maximum moving average change from baseline to Day 10 of 3 consecutive 15-minute blood pressure measurements across the first 4 hours after the morning (AM) and evening (PM) doses. In this method, the LS means of three consecutive time points over the 4 hour period were determined and the maximum LS mean was used for the endpoint. Blood pressure was determined using continuous monitoring at rest. Increased values represent an increase in hypertensive severity. | The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (maxMAΔ in blood pressure). | Posted | Least Squares Mean | 95% Confidence Interval | mmHg | Up to 4 hours postdose on Days 1 and 10 |
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|
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| Secondary | Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours (AUC0-12hr) of MK-8457 | AUC0-12hr is an estimate of total plasma exposure to study drug over the dosing interval (12hr). Plasma concentrations of MK-8457 were determined on Day 1 (after initial dosing) and Day 10 (after multiple dosing). The placebo group is not included; this endpoint evaluated only the MK-8457 group. | The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (AUC0-12hr). | Posted | Geometric Mean | Geometric Coefficient of Variation | nM*hr | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10 |
|
|
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| Secondary | Maximum Concentration (Cmax) of MK-8457 | Maximum plasma concentrations of MK-8521 were determined for the AM dose on Day 1 and Day 10. The placebo group was not included; this endpoint evaluated only the MK-8457 group. | The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (Cmax). | Posted | Geometric Mean | Geometric Coefficient of Variation | nM | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; 24 hrs post-AM dose on Day 10 |
|
|
|
| Secondary | Time to Maximum Concentration (Tmax) of MK-8457 | Tmax was determined for the AM dose on Day 1 and Day 10. The placebo group was not included; this endpoint evaluated only the MK-8457 group. | The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (Tmax). | Posted | Median | Full Range | hr | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; 24 hrs post-AM dose on Day 10 |
|
|
|
| Secondary | Trough Plasma Concentration (Ctrough) of MK-8457 | The lowest plasma concentration reached by the drug prior to the next administration was determined for Day 1 (after initial dosing) and Day 10 (after multiple dosing). The placebo group was not included; this endpoint evaluated only the MK-8457 group. | The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (Ctrough). | Posted | Geometric Mean | Geometric Coefficient of Variation | nM | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; pre-AM dose on Day 5 or 6 |
|
|
|
| Primary | Number of Participants Who Experienced at Least One Adverse Event (AE) | An AE is defined as any unfavorable and unintended medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. | The safety population consisted of all participants who received at least one dose of the investigational drug. | Posted | Number | Participant | Up to 70 days |
|
|
|
| Primary | Number of Participants Who Discontinued the Study Medication Due to an AE | An AE is defined as any unfavorable and unintended medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. | The safety population consisted of all participants who received at least one dose of the investigational drug. | Posted | Number | Participant | Up to 70 days |
|
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|
| 0 |
| 31 |
| 8 |
| 31 |
| EG001 | Placebo | Participants received Placebo for MK-8457 for 10 days | 0 | 29 | 9 | 29 |
| Tinnitus | Ear and labyrinth disorders | MedDRA v 15.0 | Systematic Assessment |
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| Bloating | Gastrointestinal disorders | MedDRA v 15.0 | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA v 15.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA v 15.0 | Systematic Assessment |
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| Energy decreased | General disorders | MedDRA v 15.0 | Systematic Assessment |
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| Flu-like symptoms | General disorders | MedDRA v 15.0 | Systematic Assessment |
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| Swelling of fingers | General disorders | MedDRA v 15.0 | Systematic Assessment |
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| Venipuncture site pain | General disorders | MedDRA v 15.0 | Systematic Assessment |
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| Viral upper respiratory tract infection | Infections and infestations | MedDRA v 15.0 | Systematic Assessment |
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| White blood cell count abnormal | Investigations | MedDRA v 15.0 | Systematic Assessment |
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| Knee pain | Musculoskeletal and connective tissue disorders | MedDRA v 15.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA v 15.0 | Systematic Assessment |
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| Lightheadedness | Nervous system disorders | MedDRA v 15.0 | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA v 15.0 | Systematic Assessment |
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| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA v 15.0 | Systematic Assessment |
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| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA v 15.0 | Systematic Assessment |
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| Dry skin | Skin and subcutaneous tissue disorders | MedDRA v 15.0 | Systematic Assessment |
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| Deep vein thrombosis | Vascular disorders | MedDRA v 15.0 | Systematic Assessment |
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The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission.
| DBP - AM (n=29,28) |
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| DBP - PM (n=29,27) |
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Treatment comparison of maxMAΔ in SBP from baseline to Day 10 after PM dosing |
| Linear mixed effects model |
The model contained period and treatment as fixed effect, Day -1 baseline as a fixed continuous covariate, and participant as random effect. |
| Mean Difference (Final Values) |
| -0.94 |
| 2-Sided |
| 90 |
| -5.68 |
| 3.81 |
| Superiority or Other |
| Treatment comparison of maxMAΔ in DBP from baseline to Day 10 after AM dosing | Linear mixed effects model | The model contained period and treatment as fixed effect, Day -1 baseline as a fixed continuous covariate, and participant as random effect. | Mean Difference (Final Values) | 5.26 | 2-Sided | 90 | 0.81 | 9.71 | Superiority or Other |
| Treatment comparison of maxMAΔ in DBP from baseline to Day 10 after PM dosing | Linear mixed effects model | The model contained period and treatment as fixed effect, Day -1 baseline as a fixed continuous covariate, and participant as random effect. | Mean Difference (Final Values) | -1.69 | 2-Sided | 90 | -4.55 | 1.17 | Superiority or Other |